Glioblastoma (GB) is the most aggressive primary malignant brain tumor and is associated with short survival. O-GlcNAcylation is an intracellular glycosylation that regulates protein function, enzymatic activity, protein stability, and subcellular localization. Aberrant O-GlcNAcylation is related to the tumorigenesis of different tumors, and mounting evidence supports O-GlcNAc transferase (OGT) as a potential therapeutic target. Here, we used two human GB cell lines alongside primary human astrocytes as a non-tumoral control to investigate the role of O-GlcNAcylation in cell proliferation, cell cycle, autophagy, and cell death. We observed that hyper O-GlcNAcylation promoted increased cellular proliferation, independent of alterations in the cell cycle, through the activation of autophagy. On the other hand, hypo O-GlcNAcylation inhibited autophagy, promoted cell death by apoptosis, and reduced cell proliferation. In addition, the decrease in O-GlcNAcylation sensitized GB cells to the chemotherapeutic temozolomide (TMZ) without affecting human astrocytes. Combined, these results indicated a role for O-GlcNAcylation in governing cell proliferation, autophagy, cell death, and TMZ response, thereby indicating possible therapeutic implications for treating GB. These findings pave the way for further research and the development of novel treatment approaches which may contribute to improved outcomes and increased survival rates for patients facing this challenging disease.
胶质母细胞瘤（GB）是最具侵袭性的原发性恶性脑肿瘤，与患者生存期短密切相关。O-GlcNAc糖基化是一种细胞内糖基化修饰，可调控蛋白质功能、酶活性、蛋白稳定性及亚细胞定位。异常的O-GlcNAc糖基化与多种肿瘤的发生发展相关，越来越多的证据表明O-GlcNAc转移酶（OGT）是潜在的治疗靶点。本研究采用两种人GB细胞系，并以原代人星形胶质细胞作为非肿瘤对照，探讨O-GlcNAc糖基化在细胞增殖、细胞周期、自噬和细胞死亡中的作用。研究发现，高O-GlcNAc糖基化通过激活自噬促进细胞增殖增强，且该过程不依赖于细胞周期改变；而低O-GlcNAc糖基化则会抑制自噬、促进细胞凋亡性死亡并降低细胞增殖。此外，降低O-GlcNAc糖基化水平可增强GB细胞对化疗药物替莫唑胺（TMZ）的敏感性，且不影响人星形胶质细胞。综上，这些结果表明O-GlcNAc糖基化在调控细胞增殖、自噬、细胞死亡及TMZ应答中发挥关键作用，提示其可能具有治疗GB的潜在价值。该发现为进一步探索和开发新型治疗方法奠定了基础，有望改善这类难治性疾病患者的预后并提高其生存率。
肿瘤(癌症)患者之家